At the Cutting Edge
Models of ovarian cancer—Are we there yet?

https://doi.org/10.1016/j.mce.2005.03.019Get rights and content

Abstract

Ovarian cancer is the most lethal of all gynecological cancers and arises most commonly from the surface epithelium. Successful clinical management of patients with epithelial ovarian cancer is limited by the lack of a reliable and specific method for early detection, and the frequent recurrence of chemoresistant disease. Experimental models are of crucial importance not only to understand the biological and genetic factors that influence the phenotypic characteristics of the disease but also to utilize as a basis for developing rational intervention strategies. Ovarian cancer cell lines derived from ascites or primary ovarian tumors have been used extensively and can be very effective for studying the processes controlling growth regulation and chemosensitivity or evaluating novel therapeutics, both in vitro and in xenograft models. While our limited knowledge of the initiating events of ovarian cancer has restricted the development of models in which the early pathogenic events can be studied, recent advances in the ability to manipulate gene expression in ovarian surface epithelial cells in vitro and in vivo have begun to provide insights into the molecular changes that may contribute to the development of ovarian cancer. This review highlights the strengths and weaknesses of some of the current models of ovarian cancer, with special consideration of the recent progress in modeling ovarian cancer using genetically engineered mice.

Introduction

Epithelial ovarian cancer has less than a 1% life-time risk, yet is the most lethal of the gynecologic malignancies (American Cancer Society, 2003). This is due in part to the late diagnosis following a commonly asymptomatic early disease, as well as the high rate of chemo-resistance, which limits treatment of recurrent disease. Current research efforts are focused on improving our understanding of the etiology and early stages of the disease, as well as in the development and evaluation of novel therapeutics. While the ultimate goal of ovarian cancer models is to provide a system for the discovery and testing of novel therapeutics, the process of developing and refining models to more accurately reflect human ovarian cancer forces us to understand the disease in greater detail.

The past 5 years have yielded remarkable progress in the development of models of ovarian cancer, including in vitro transformed human and murine ovarian surface epithelial cells, xenotransplanted cancer cells with defined histopathological features, and the first transgenic model of epithelial ovarian cancer. From these models has come the observation that inactivation/activation of different signalling pathways can lead to the emergence of ovarian cancers with different phenotypes and histologies. While each of these models has unique strengths, there remains significant restrictions on their relevance to human disease. Tumor development from xenografted cells is achieved only in immune-compromised animals. The degree to which in vitro transformation of human and mouse cells faithfully represents the process in vivo remains unknown. Early onset of tumor development in the transgenic model precludes investigation of mechanisms of disease initiation or preventive interventions. In addition, the inability to simply and accurately monitor tumor progression of intraperitoneal disease remains a challenge for all models. Despite these limitations, the recent advances in model development have brought much excitement to the study of ovarian cancer, and the application of genetics and targeting approaches will undoubtedly improve and refine these models and their relevance to human ovarian cancer. This review examines xenograft, cell culture and transgenic models of ovarian cancer with particular emphasis on recent advances and remaining challenges.

Section snippets

Exploring the diversity of human ovarian cancers in xenograft models

Xenografting human cancer cells into immune-deficient mice has been a popular and useful research tool since the late 1960s (Rygaard and Povlsen, 1969), and has been essential for analyzing the tumorigenicity of cells, the histology of tumors that they form, and in the evaluation of therapeutics. Human ovarian cancer cell xenografts are possibly the most widely used research models for the study of ovarian cancer as they are derived from naturally occurring clinical cases, and are therefore

Modeling early ovarian cancer with ovarian surface epithelial cells

While xenograft models using human cancer cell lines may shed light on the nature and behavior of advanced human ovarian cancers, there is great interest in understanding the earlier steps of ovarian cancer and to develop models of ovarian cancer which will reflect both early and late stages of disease. The ability to isolate and culture relatively pure populations of ovarian surface epithelial (OSE) cells from human (Auersperg et al., 1984, Gregoire et al., 1998, Nitta et al., 2001, Tsao et

Transgenic mouse models: is the MISIIR promoter the answer?

One of the biggest challenges of creating a mouse model of ovarian cancer that adequately recapitulates the human disease has been not only identifying the appropriate genetic pathways to target, but determining how to manipulate these pathways in a manner that is spatially and temporally defined. The development of traditional transgenic models of ovarian cancer has been difficult due to the lack of suitable promoters that can drive transgene expression exclusively to the ovarian surface

Exploiting the Cre–loxP recombination system

The difficulty in finding suitable promoters for conventional transgenic models of epithelial ovarian cancer has been circumvented by the exploitation of the Cre–loxP recombination system. Model systems based on this technology have significant advantages over the other model systems, and although only two have been reported thus far, these models have proven to be highly informative. The Cre–loxP system consists of cre, a recombinase, and its 34 bp binding site, loxP. Portions of DNA flanked on

Are we there yet?

During the past 5 years, the greatest advances in ovarian cancer models have been the generation of transgenic mouse models, the development of genetically defined models in murine and human OSE cultures, and the observation that inactivation/activation of different signalling pathways can lead to the emergence of ovarian cancers with different phenotypes and histologies. Exciting future prospects include the detailed examination of the role in tumorigenesis of relevant signalling pathways

Summary

In this review, we have highlighted recent advances in ovarian cancer models including xenografts of human ovarian cancer cell lines, the genetic manipulation of human, mouse, and rat ovarian surface epithelial cell lines and the development of mouse transgenic models. While it is unlikely that any of these models will perfectly reflect the human disease, each model comes with both strengths and weaknesses (Fig. 3). The future of ovarian cancer models will be through the refinement of these

Acknowledgements

The authors thank Olga Collins and Colleen Crane for their expert technical assistance with the histology and immunohistochemistry data presented in this review. We are also grateful to Drs. Lesley Dunfield and Teresa Woodruff for their critical reviews of the article.

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